Among the diseases widely called as adult diseases (diseases in persons of middle or advanced age) or life-style related diseases, those such as abnormal carbohydrate/lipid metabolisms; impaired glucose tolerance, diabetes, hyperlipemia and high-blood pressure related thereto; and abdominal obesity form clusters of the diseases that are recognized as metabolic syndromes. Patients with metabolic syndromes not only have a low quality of life due to the various symptoms but also have higher lethal risk or a risk of developing fatal vascular disorders such as arterial sclerosis as compared with healthy people. The diseases or symptoms such as impaired glucose tolerance, diabetes, hyperlipemia and high-blood pressure are just the tip of the iceberg of metabolic syndromes as a whole. Though it is important to provide the treatment corresponding to each disease/symptom, it is thought that the most effective method to diminish a lethal risk is to prevent/treat overall syndromes by preventing/treating abnormalities that deeply relate to the pathogenic mechanism of metabolic syndromes. Nevertheless, such therapeutic agents and/or therapeutic methods have not yet been found until now.
Through the achievement of the recent multicenter studies, the abnormalities relating to adiponectin that is expressed/generated in adipose tissues and secreted in the blood are paid attention as the most important cause of metabolic syndromes. Adiponectin was found as a secreted protein that is specifically expressed in adipose tissues and has a similar structure to that of complements (Non-patent Literatures 1 and 2). Patients with metabolic syndromes develop hypoadiponectinemia and, for example, it is reported that hypoadiponectinemia is a risk factor independent of other factors of type II diabetes (Non-patent Literature 3). In addition to the diseases such as metabolic syndromes and those that relate to abnormal carbohydrate metabolism, e.g. diabetic retinopathy, gestational diabetes mellitus and polycystic ovary syndrome, hypoadiponectinemia or the decreased expression of adiponectin mRNA in tissues is reported in the diseases such as cardiovascular diseases, e.g. ischemic heart disease, myocardial infarction, angina pectoris, vascular stenosis, and hypertrophic cardiomyopathy; vascular diseases, e.g. coronary artery heart disease, coronary artery disease, cerebrovascular disorder and peripheral artery disease; liver diseases, e.g. hepatic fibrosis, liver cirrhosis, hepatic inflammation, non-alcoholic/nonviral steatohepatitis and fatty liver disease (NASH and NAFLD), alcoholic fatty liver and alcoholic hepatic disorder; cancers/malignant neoplasm, e.g. endometrioma, uterine leiomyoma and lung cancer; endocrine/metabolic diseases, e.g. Cushing's syndrome, HIV-related lipodystrophy syndrome, thyroidal dysfunction and atrophy of adipose tissues; and neurogenic emaciation, bulimia nervosa, and nephropathy. It is also reported, including the reports in the level of basic experiments, that the development of the diseases due to lack of adiponectin is seen and there is a possibility of treatment by supplying adiponectin.
Particularly, in the level of the basic experiments, effects of decreasing lipids in the blood and blood glucose and preventing body weight gain are seen in model animals by administering recombinant adiponectin, and, therefore, its possibility as a therapeutic agent of metabolic syndromes is reported (Non-patent Literatures 4 and 5). Besides it, it is also reported that adiponectin has an anti-atherogenic action acting directly to blood vessels, such as effects of: inhibiting foaming or adhesion of monocytes; inhibiting proliferation of smooth muscle cells; and inhibiting intimal thickening (Non-patent Literature 6). Further, its possibility as a therapeutic agent of hepatic diseases is also reported since it inhibits: hepatic fibrosis in the disease models induced by chemical substances; activation of stellate cells that play a large part of hepatic fibrosis; hepatic inflammation induced by endotoxin, and the like (Non-patent Literatures 7 and 8). It is also reported that adiponectin has an anti-inflammatory action, and it is paid attention as a therapeutic agent that mimics exercise effects, since adiponectin induces 5′AMP-activated kinase activity to tissues, said activity which is induced during exercise and considered to be important in the molecular mechanism that brings exercise benefits. Thus, adiponectin is paid attention as a preventive/therapeutic agent of various fatal diseases. However, administration method of adiponectin to patients is expected to be injection just as the method of physiologically active substances such as insulin, and it is a therapeutic method with pain and time-consuming. Therefore, in the present situation, it is desired to develop a therapeutic agent such as those that can induce expression of adiponectin by directly acting on adipose cells and increase its secretion in the blood.
Non-patent Literature 1: A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995 Nov. 10; 270(45):26746-9
Non-patent Literature 2: AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 1996 May 3; 271(18):10697-703
Non-patent Literature 3: Decreased serum levels of adiponectin are a risk factor for the progression to type 2 diabetes in the Japanese Population: the Funagata study. Diabetes Care 2003 July; 26(7):2015-20
Non-patent Literature 4: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 2001 August; 7(8):941-6
Non-patent Literature 5: The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat. Med. 2001 August; 7(8):947-53
Non-patent Literature 6: Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2002 Nov. 26; 106(22):2767-70
Non-patent Literature 7: Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology. 2003 December; 125(6):1796-807
Non-patent Literature 8: Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice. Hepatology. 2004 July; 40(1):177-84